The present invention relates to a macromolecular endoplasmic reticulum in which surface charge is fixed to negative.
It is possible to utilize the macromolecular endoplasmic reticulum of the present invention as a carrier of medicine, enzyme, hemoglobin, etc. in industrial fields or medical fields
There are many reports for trying to enhance the effectivity of useful materials such as medicine and enzyme by capsulizing in fine capsules. In the initial trials, synthetic macromolecular compounds such as polystyrene and nylon were used as membrane materials.
However, since these materials were toxic and they caused thrombus because they had large grain size, they were unusable.
Recently, it is noted to use a fine microcapsule (endoplasmic reticulum) made of natural phospholipid as membrane materials having little toxicity, particularly, as a carrier of medicine. The grain size of the micro-capsule can be optionally adjusted to 0.02 .mu.m to a few .mu.m. Then the problems such as thrombosis are evitable by determination of proper grain size. However, there are problems that the endoplasmic reticulum has neither shelf stability nor retention in blood because it is physically and chemically unstable in vivo and it tends to decompose easily.
The other hand, hemoglobin carrying oxygen in the body of mammals is utilized as an agent for carrying, storing or absorbing oxygen. Particularly, it is often used as materials of a oxygen carrying liquid. In the body, hemoglobin is contained in red blood corpuscles. Imitating this, a oxygen-carrier containing a hemoglobin aqueous solution in a endoplasmic reticulum which consists of a bilayer membrane was reported (Arbing Frank Miller et al., Japanese patent publication No. 60-26092; C. Anthony Hunt, Japanese patent publication No. 58-183625; Suzuki et al., Japanese patent publication No. 62-178521). All of the endoplasmic reticula which contain hemoglobin are utilized as membrane materials using natural or synthetic non-polymerizable lipid or a lipid mixture. On such endoplasmic reticula, as described above, it is broadly examined to use not only as a carrier of a hemoglobin aqueous solution but also as that of medical supplies. Since these endoplasmic reticula are prepared from natural compounds, the safety is appreciated. However, these endoplasmic reticula can not be preserved for a long time, and they are physically and chemically unstable and easily decomposed. Particularly, the problem is that they can not be kept in blood. For this reason, it is earnestly studied to stabilize the endoplasmic reticula.
For example, as a method for stabilizing an endoplasmic reticulum, a method for polymerizing a lipid bimolecular membrane by using polymerizable phospholipids (there are many derivatives of a phosphatidylcholine type) is reported (H. Ringsdorf et al., Angewandte Chemie International Edition English, vol. 20, page 305 (1981), and others). In this method, it is tried to give physical stability to the membrane by polymerization. There is a report in which, after enclosing a hemoglobin aqueous solution in an endoplasmic reticulum obtained from one of these polymerizable phospholipids (a phosphatidylcholine derivative having diyne radicals as polymerizable residue groups) and cholesterol, the reticulum is polymerized to obtain a macromolecular endoplasmic reticulum containing hemoglobin (J. A. Hayward et al., PCT WO 85/04326).
However, for stabilizing microcapsules in a living body, especially, in blood, it is necessary to devise to maintain proper zeta potential of liposomes and keep the surface charge negative, for reducing the interaction between microcapsules and biological cells and components to a minimum. For devising it, in cases of common (non-polymerized) endoplasmic reticula and the above macromolecular endoplasmic reticulum, nonpolymerized lipids having negative electric charge, for example, non-polymerizable fatty acids, phosphatidic acid, dicetyl phosphoric acid, phosphatidyl serine have been used. However, in blood, these components are easily extracted from membranes by a component in a living body such as high density lipoprotein (HDL), so that the stability of these microcapsules was insufficient.